Preparation of pyridine alcohols



United States Patent Oilfiee 3,042,682 PREARATIUN OF PYRIDEJE ALCOHGLSRobert S. Aries, 77 South St, Stamford, Conn. N Drawing. Filed Sept. 12,1958, Ser. No. 769,573 Claims. ((31. 260- 297) This invention relates toa novel method for the preparation of pyridine alcohols and theirhomologues. More particularly, the invention concerns a novel method forthe preparation of monomethylol compounds of alkyl pyridines.

In accordance with the novel method of this invention there may beprepared in high yield and purity and with economies in time and rawmaterial consumption, alcohols of alkylpyridines, such as, for example,those having a betahydroxyethyl group at the 2-, 4-, or 6-position ofthe pyridine nucleus. Examples of such alcohols aremonomethylol-Z-picoline, monomethylol-4-picoline, and5-ethyl-Z-hydroxyethylpyridine.

In general, a hydrogen atom attached to the alphacarbon atom ofalkyl-groups substituted at the 2-, 4-, or Y 6-position of the pyridinenucleus is active due to the activating presence of the nitrogen atom ofthe pyridine nucleus. Therefore, a substance with such a hydrogen atom,for example, alpha-picoline, condenses with aldehydes to yield alcohols.In general, such a hydrogen attached to the alpha-carbon atoms ofalkyl-groups substituted at the 3- or 5-position of the pyridine nucleusis relatively or completely inactive.

As-aldehydes which may be employed for that condensation, there areincluded both aliphatic and aromatic aldehydes. However, from theindustrial standpoint, formaldehyde is the aldehyde of greatestimportance in forming such alcohols, which when formaldehyde is used asthe aldehyde, form the methylols. The reaction is particularly usefulwhen the alkyl-pyridine to be thus reacted is a compound containing amethyl group in the 2-, 4-, or 6-position of the pyridine nucleus. It isnot necessary that such a methyl group be the sole alkyl substituent, asdimethyl-pyridines, ethyl-methyl-pyridine and other pyridines containingalkyl substituents are reactive if there is at least one alkyl group inthe 2-, 4-, or 6-po'sition, and

especially if the alkyl group in such 2-, 4-, or 6-position" is a methylgroup. If more than one alkyl group exists in the 2-, 4-, or6-positions, all such alkyl groups will or may react with theformaldehyde.

The general reaction has been described in the literature, for example,by A. Ladenburg, Berichte, vol. 22, page 2583 (1889); W. Konigs and G.Happe, Berichte, vol. 34, page 1343 (1903); A. Lipp and J. Richard,Berichte, vol. 37, page 737 (1904); R. L. Frank and others, J.A.C.S.,vol. 68, page 1368 (1946).

From these articles it can readily be seen that the total reaction isquite complicated. For the case of 2- picoline the reaction may berepresented by the following sequence:

CHzCHzOH Patented July 3, 1962 Polymer Similar sequences can bepresented for the reactions of 4-methylpyridine,S-ethyl-Z-methylpyridine, and the like, with formaldehyde. I

As a result of the reactions of addition of formaldehyde in stages, andloss of Water to form vinyl type compounds which readily polymerize, theactual yield of the desired monomethylol compound is very low in thehitherto used processes.

One of the important uses of the monomethylol compounds is to preparethe corresponding vinylpyridines, but whilethe above scheme shows thatvinylpyridine is a product resulting from the dehydration of themonomethylol-pyridine, the reaction is accompanied by further reactionof the monomethylol-pyridine, and the diand tri-hydroxy-alkyl compoundsvof pyridine with additional formaldehyde to form higher methylols whichmay also, by dehydration in the course of the reaction, produceunsaturated alcohols, such as the vinyl-substituted pyridine alcohol asshown at lower right of the sequence, namely2-(alpha-vinyl-beta-hydroxyethyl) picoline.

Various attempts have been made to convert, for example, the productderived from picoline directly to vinylpyridine, but the presence in thereaction product of picoline with formaldehyde of the complex mixturesuggested in the graphical scheme shows Why the results aredisappointing as to yield even if a catalyst is used which attempts todirect the reaction toward the production of vinylpyridine. Theessential condition for the production of a high yield of vinylpyridineis the direction of the reaction to the production of a high yield ofpyridinemono-rnethylol in the absence of by-products.

It is, therefore, the primary object of this invention to obtain highyields of the pyridine monomethylol compounds, such asZ-beta-hydroxyethyl pyridine and its isomers such as4-beta-hydroxyethylpyridine and also its homologs such as5-ethyl-2-beta-hydroxyethylpyridine, and the like. The correspondingvinylpyridines obtainable by the dehydrationof the beta-hydroxyethylderivatives can be obtained in practically quantitative yield from suchbeta-hydroxyethyl derivatives. However, the essential problem, nothitherto solved, has been to obtain high yields of the beta-hydroxyethylderivatives. These intermediates are stable, easily stored compounds,whereas the corresponding vinyl derivatives areso reactive andpolymerize so rapidly that they must be kept at low temperatures even inthe presence of a polymerization inhibitor.

In accordance with one known method, for example, methylpyridines aretreated with formaldehyde at high pressure at elevated temperatures inthe presence of a catalyst, followed by rapid cooling of the reactionproduct, to obtain mixtures of the hydroxyethylpyridine and of thevinylethylpyridine, in which the vinyl compound may be present to theextent of 36%. In such mixtures the separation of the monomethylol.derivative and the vinyl derivative presents problems because of thegreat "utes, advantageously from merization.

In accordance with the present invention, it has been found,surprisingly and unexpectedly, that it is possible The preferred mode ofcarrying'ont the novel process of my invention is illustrated by thefollowing examples, but the invention is not to be considered as limitedthereto.

EXAMPLE 1 some alkylpyridine necessarily remains unconverted, but

is easily recovered for re-use by steam distillation.

When formaldehyde is employed, it may be used as a solution, forexample, the commercial 37% solution in "water, or as the anhydrouspolymers, paraformaldehyde or trioxane. When the aqueous solution offormaldehyde is used, water is the solvent, but any other solvent'mayalso-be used, provided it does not react either .With'the reactants orwith the products... A suitable solvent for eirample is a completelysaturated hydrocarbon such nwheptane or tetralin. i Thetemperature ofappears desirable, it may be employed up to about 15 O-atto 0,8:1,andpreferably between 0.35:1 and 0.65:1. The reactiontime is very brief,generally less than 10 min- 3 to 9 minutes, and 'preferafbly from 3'to7minutes. L I 1 Following the reaction, the reaction product 1s1mmediately cooled to. below about100 C., and the monomethylolpyrid ineis separated.

the reaction is maintained between "aboutZOO and 320 0., advantageouslybetween about 210? and 300 C., and preferably between about 230 270 C.While the use of superatmospheric pressure 'is not required, in suchcases where the use. of pressure to obtain a monomethylolpyridine whichis substantially 5 free m ViIIYIPYI'idiIIeS and hence from thedetrimental In a series of experiments, summarized in Table 1, 0.1tendency of the latter to polymerize spontaneously when mol of thealkylpyridine was mixed with 0.05 mole of present. Thus, the'monomethylolpyridines Obtained i formaldehyde, either as the 37%aqueous solution or as accordance with the novel method of thisinvention are paraformaldehyde, so as to contain 0.05 mole of actual ofhigh purity and stability, and can be shipped and 10 CH O or of itspolymer. j stored for prolonged periods of time with no deteriora- The.mixture, prewarmed to 100 C., was placed in :1 tion. The presentprocess, moreover, eliminates the use half liter stainless steelautoclave, the air was replaced of high pressures and of catalysts, thusresulting in furby nitrogen, and the autoclave was closed and immersedther economies in time .and materials. 7 in a large volume molten metalbath held at the desired In accordance with my novel method, thereaction be.- temperature, and the charge in the reactor was subjected Itween an alkylpyridine containing 'at least one methyl to the desiredtemperature/for from l to 35 minutes, group in the 2-, 4-, or 6-positionis carriedout at elevated and the reactor was then 'liftedout and cooledas rapidly temperatures, while keeping the molar ratio of aldehyde aspossible. The cooled charge was then diluted with wato alkylpyridinebelow 1:1, and preferably as low as 0.5: l, .ter, transferred to adistillation flask, and steam distilled and at ordinary pressure. Underthese conditions, extrato remove unconverted alkylpyridine andformaldehyde. ordinarily high yields of monomethylol pyridines are ob-The residue was then distilled at a pressure of 3 mm. of .tained,ranging from 93 to 99 percent, as indicated in mercury at97-100" C. toobtain the'jhydroxyethylpyriaccompanying'Table' 1, while the presence ofvinylpyridine as adistillate, while a residue of high-boiling materialdines and high boiling impurities and lay-product's is held remained inthe flask. e to a few percent. Moreover, no catalyst is required, andThe residue of high boiling materials was weighed. the only pressurepresent'is that developed by heating in The results of theseexperimentsiare-set forth in the folclosed vessels used'to reduce lossof aldehyde. Morelowing Table 1:

' Table 1 Conversion, Mole Yield of Converted Mole Percent PyridineAlkyl-Pyridine Type of Formal- Temp, Time r dehyde O. (min) Mono- HighPyr. 011 0" Vinyl Moth: Boiling Pyr ylol Com- POUlCldS 37%solution 7 21015 20.3 87.3 '03 94.8 4.9 d 230 10 22.8 39.3 0.0 96.9 3.1 250 5 25.5 96.7 0.0 99.0 1.0 250 10 28.0 9 8.1 4.0 94.0 2.0 280 3 27.7 98.7 2.5 96.01.5 310 1 28.4 93.2 2.1 96.4 1.5 240 5 20.7 94.8 0.9 97.5 1.6 269 5 28.499.0 2.0 95.1 2.9 230 5 23.5 98.6 1.5 97.0 1.5

280 10 27.3 99.3 4.1 93.1 2.8 320 2 28.4 99.7 3.2 95.2 1.6 1:. 310 127.1 93.2 3.3 94.2 2.5 aldehyde .4mimlirw d 280 3 29.1 98.7 3.8 93.8 2.4Z-methyl-Sethyl pyrido' 250 10 23.1 93.5 2.0 94.1 3.9 7 dine. over,under the conditionsemployed in my novel process, EXAMPLE 2 The reactionof Example 1 can be carried out in a continuous apparatus, such as isrequired on the commercial scale. The reaction was carried out on aconsiderably larger scale, using as raw material a mixture of 2-picolineand 37% aqueous formaldehyde, with the ratio of CH O :C H NCH =0.5:L'Ihe'mixture'was fed by a positive displacement pump througha tubularpreheater,.

heated by Dowtherm, whereIit acquired-the desired temperature, to a highpressure reactor consisting of a jacketed stainless steel pipe withflanged ends. The jacket was heated by circulating Dowtherm to maintainthe desired temperature. The charge was fed through a bottom inletanddischarged through a Water cooled metal condenser to a metal receiver.The Whole system was first flushed thoroughly with nitrogen and thenpressured to 100 atmospheres with nitrogen supplied from. a cylinder.The receiver was in its upper portion connectedwith a vent valve set atatmospheres to release excess pressure. A slight flow of nitrogen'fromthe pressure cylinder was maintained by means of a needle valvethroughout the 'run to hold the pressure and to assure positive actionof the vent valve. Theresidence time in the reactor when the feed was 32grams per minute was 4.5 minutes. The products obtained in a 3 hour rununder these conditions were diluted with an equal volume of water andthen heated in a still to 100 C. to remove water and with it unchanged2-picoline and formaldehyde. The residue was distilled under vacuum at-3 mm. of mercury absolute pressure and 97-100 C. to iractionate out the2-hydr0xyethylpyridine. From 4070 grams of 2-picoline, there wereobtained 5820 grams of total reaction product. This reaction productyielded:

Grams Recovered 2-picoline 2940 2-vinylpyridine 14Monomethylol-Z-picoline 1341 Z-(alpha-hydroxymethyl)vinylpyridine 7Dimethylol-Z-picoline 47 Polymerized residue 55 Water and loss 1416Monomethylol-Z-picoline was thus obtained in 89.6 molar percent yield.The 10.4% loss includes both the conversion to undesired compounds andalso the una scale.

I claim:

1. Method for the preparation of monomethylol derivatives ofalkylpyridines which comprises reacting an alkylpyridine selected fromthe group consisting of Z-picoline, 4picoline, and5-ethyl-2-methylpyridine with formaldehyde under a blanket of an inertgas at a pressure between about 1 and about 150 atmospheres, at atemperature between about 200 C. and about 320 C., for a period betweenabout 3 and about 7 minutes, the molar ratio of formaldehyde toalkylpyridine being between 0.35:1 and 0.65: 1, then rapidly cooling thereaction mixture to below 100 C., and recovering the monomethylolderivative therefrom.

, 2. The method of claim 1 in which the alkyl pyridine is 2-picoline.

3. The method of claim 1 in which the alkylpyridine is 4-picoline.

methylol-Z-picoline therefrom.

avoidable refining losses when operating on so limited v ReferencesCited in the file of this patent UNITED STATES PATENTS 2,512,660 MahanJune 27, 1950 2,698,848 Mahan Jan. 4, 1955 2,754,300 MacLean et al July10, 1956 OTHER REFERENCES Profit: Chem. Abstracts, vol. 51, column 6629(1957).

1. METHOD FOR THE PREPARATION OF MONOMETHYLOL DERIVATIVES OFALKYLPYRIDINES WHICH COMPRISES REACTING AN ALKYLPYDIDINE SELECTED FROMTHE GROUP CONSISTING OF 2-PICOLINE, 4-PICOLINE, AND5-ETHYL-2-METHYLPYRIDINE WITH FORMALDEHYDE UNDER A BLANKET OF AN INERTGAS AT A PRESSURE BETWEEN ABOUT 1 AND ABOUT 150 ATMOSPHERES, AT ATEMPERATURE BETWEEN ABOUT 200*C. AND ABOUT 320*C., FOR A PERIOD BETWEENABOUT 3 AND 7 MINUTES, THE MOLAR RATIO OF FORMALDEHYDE TO ALKYLPYRIDINEBEING BETWEEN 0.35:1 AND 0.65:1, THEN RAPIDLY COOLING THE REACTIONMIXTURE TO BELOW 100*C., AND RECOVERING THE MONOMETHYLOL DERIVATIVETHEREFROM.